WO2023047399A1 - Conjugués cannabinoïdes-lipides, leurs procédés de production et leurs utilisations - Google Patents

Conjugués cannabinoïdes-lipides, leurs procédés de production et leurs utilisations Download PDF

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WO2023047399A1
WO2023047399A1 PCT/IL2022/051012 IL2022051012W WO2023047399A1 WO 2023047399 A1 WO2023047399 A1 WO 2023047399A1 IL 2022051012 W IL2022051012 W IL 2022051012W WO 2023047399 A1 WO2023047399 A1 WO 2023047399A1
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conjugate
cannabinoid
acid
thc
cbd
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Daniel Offen
Nataly YOM-TOV
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Ramot At Tel-Aviv University Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A61K47/544—Phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin

Definitions

  • the present disclosure concerns cannabinoid-lipid conjugates.
  • WO2017/106957 describes lipid linked pro-drugs and their therapeutic use.
  • WO20 19/200043 describes lipid prodrugs that self-assemble into lipid microbubbles or liposomes.
  • the prodrug-loaded microbubbles or liposomes can be active intracellularly using an external stimulus, for example, ultrasound waves.
  • WO202191477 describes lipid conjugates for the delivery of a molecule of interest such as a drug moiety, the conjugate comprising a linker group such as ester, ether or carbamate.
  • the lipid conjugate can be formulated in a drug delivery vehicle such as a lipid nanoparticle (LNP).
  • LNP lipid nanoparticle
  • W02021/184010 describes nano-formulations of cannabidiol (CBD) and other cannabinoids as well as method of treating specific ocular diseases using the nanoformulations.
  • a cannabinoid-phospholipid conjugate having the general formula (I): wherein A is a cannabinoid and PL is a phospholipid (PL); and wherein the cannabinoid (A) is covalently linked, via a cleavable linker, to a polar head group of the PL.
  • the cannabinoid A is linked to the cleavable linker at a position occupied by a hydroxyl group when said cannabinoid A is in free form.
  • the cannabinoid A is linked to the cleavable linker through an oxygen bridge at a position occupied in the cannabinoid by a hydroxyl group when said cannabinoid A is in free form; the method comprises, in its broadest scope, reacting a phospholipid (PL) with the cannabinoid (A) in a reaction method involving the formation of an intermediate conjugate with maleic anhydride.
  • PL phospholipid
  • A cannabinoid
  • the method comprises:
  • a cannabinoid-phospholipid conjugate as disclosed herein for use as a vehicle for releasing said cannabinoid, in free form, at a target site.
  • a method for delivering a cannabinoid to a target site in a subject in need thereof comprises administering to said subject an amount of a cannabinoid-phospholipid conjugate as disclosed herein.
  • Figure 1 is a Liquid Chromatography Mass Spectroscopies of the exemplary intermediate DLPE-MA, showing the intermediate peak at 4.119 minutes.
  • Figures 2A-2C provide Nuclear Magnetic Resonance (NMR) spectroscopies of the non-limiting exemplary final DLPE-MA-CBD conjugate of, respectively, the 'H- NMR (Fig. 2 A), °C-NMR (Fig. 2B) and 31 P-NMR (Fig. 2C).
  • NMR Nuclear Magnetic Resonance
  • Figures 3A-3C provide high pressure liquid chromatogram (HPLC) (Fig. 3A), UV absorbance spectrum (Fig. 3B) and Nuclear Magnetic Resonance ('H-NMR, 400MHz, Fig. 3C) of exemplary final DLPE-MA-CBD conjugate according to nonlimiting Example IB.
  • HPLC high pressure liquid chromatogram
  • Fig. 3B UV absorbance spectrum
  • Fig. 3C Nuclear Magnetic Resonance
  • Figures 4A-4B provide a computational presentation of DLPE-MA-CBD conjugate in accordance with an example of the present disclosure, illustrating the phosphorous group to which the two fatty acid chains are linked, the cleavable linker and the CBD group (Fig. 4A) and the spatial configuration of the conjugate, similarly pointing at the phosphorous group to which the two fatty acid chains are linked, the cleavable linker and the CBD group (Fig. 4B).
  • Figures 5A-5C provide high pressure liquid chromatogram (HPLC) (Fig. 5A), UV absorbance spectrum (Fig. 5B) and Nuclear Magnetic Resonance ('H-NMR, 400MHz, Fig. 5C) of exemplary final DLPE-MA-CBN conjugate according to nonlimiting Example 2.
  • the presently disclosed subject matter is based on the identification of a cleavable, yet covalent, linkage between a lipid moiety and a cannabidiol that allows for the enzymatic release of the cannabidiol once within the suitable environment (e.g. within a living body).
  • a conjugation a lipid moiety to one of the cannabidiol hydroxyl groups (when the cannabidiol is unbound to any moiety), via a maleic acid linkage (“linker”) provides a unique spatial configuration, as illustrated in the non-limiting example of Figures 2A-2B, that permits access to enzymatic cleavage and release of the cannabinoid, once brought into proximity with the enzyme.
  • a cannabinoid-phospholipid conjugate having the general formula (I): wherein A is a cannabinoid and PL is a phospholipid (PL); and the cannabinoid (A) is covalently linked, via a cleavable linker, to a polar head group of the PL.
  • the cannabinoid A is linked to the cleavable linker at a position occupied by a hydroxyl group present in the cannabinoid, when the cannabinoid A is in free form.
  • cannabinoid refers to a chemical substance, preferably low molecular weight compound, that shows direct or indirect activity on the endocannabinoid system, e.g., to induce receptors and downstream effectors of the endocannabinoid system. It is to be understood that the term “cannabinoid” as defined herein includes but is not limited to purified food and pharmaceutical grade substances, which may be obtained by purification from a natural source or via synthetic means.
  • the cannabinoid may be a purified isolated individual cannabinoids, synthetic cannabinoids and analogues thereof, cannabidiol (CBD) or analogues thereof, tetrahydrocannabinol (THC) or analogues thereof.
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • a low molecular weight compound is one having a weight of equal or less than l,000kDa.
  • the cannabinoid is a cannabidiol (2-[(lA,6A)-6-Isopropenyl-3-methylcyclohex-2-en-l-yl]-5-pentylbenzene- 1,3-diol, also known by the abbreviated name "CBD”) or a CBD functional analogue thereof.
  • CBD cannabidiol
  • a “functional analogue” it is to be understood to include any compound (preferably low molecular weight compound) that binds to a cannabidiol receptor, with either a same or a greater potency as compared to the respective natural cannabinoid, to which it is analogous.
  • the functional analogue also shares a degree of structural similarity with respective natural cannabinoid.
  • CBD is used herein to collectively refer to the naturally occurring CBD as well as to CBD analogues (synthetic or semi synthetic).
  • CBD analogues
  • cannabinoids examples include, without being limited thereto, CBD, the synthetic Cannabidiol-dimethylheptyl (CBD-DMH), the phytocannabinoids Cannabidivarin (CBDV), Cannabidivarinolic acid (CBDVA), cannabidiolic acid (CBDA), Cannabidiol monomethyl ether (CBDM), cannabidiolquinones (CBDQ), Cannabidiol hydroxy quinone (CBDHQ), and abnormal CBD (Abn-CBD) [Paula Morales, Patricia H.
  • the cannabinoid is the natural CBD.
  • the cannabinoid is a tetrahydrocannabinol (THC) including also known by the abbreviated name "delta9-THC”, “delta8-THC” or “THC”) or a THC functional analogue thereof.
  • THC tetrahydrocannabinol
  • THC is used herein to collectively refer to the naturally occurring THC as well as to THC analogues (including synthetic or semi synthetic).
  • delta9- THC will be used.
  • THC examples include, without being limited thereto, include delta9-THC, delta8-THC, trans-DELTAlO-tetrahydrocannabinol (trans-DELTAlO-THC), cis-DIO- tetrahydrocannabinol (cis-DELTAlO-THC), tetrahydrocannabinolic acid C4 (THCA- C4), tetrahydrocannbinol C4 (THC-C4), tetrahydrocannabivarinic acid (THCVA), tetrahydrocannabivarin (THCV), DELTA8-tetrahydrocannabivarin (DELTA8-THCV), DELTA9-tetrahydrocannabivarin (DELTA9-THCV), Delta-9-tetrahydrocannabinolic acid B (DELTA9-THCA-B), tetrahydrocannabiorcolic acid (THCA-C1), t
  • the cannabinoid is the delta9-THC.
  • the cannabinoid is a cannabigerol (CBG) or a functional analogue thereof.
  • the CBG or functional analogue thereof is selected from the group consisting of cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerovarinic acid (CBGVA), cannabigerol monomethyl ether (CBGM), cannabigerovarinic acid (CBGVA), cannabigerolic acid monomethylether (CBGAM), cannabigerovarin (CBGV), and quinone of CBG [Kogan NM, Peters M, Mechoulam R. Cannabinoid Quinones-A Review and Novel Observations. Molecules. 2021 Mar 21 ;26(6): 1761. doi: 10.3390/molecules26061761. PMID: 33801057; PMCID: PMC8003933],
  • cannabinoids that fall within the scope of the presently disclosed subject matter include, without being limited thereto, cannabichromene (CBC), cannabichromanone (CBCN), cannabichromenic acid (CBCA), cannabivarichromene (CBCV), cannabichromevarinic acid (CBCVA), cannabinol (CBN), cannabinolic acid (CBNA), cannabinol methyl ether (CBNM), cannabinol C4 (CBN-C4), cannabinol C2 (CBN-C2), cannabinol Ci (CBN-Ci), cannabinodiol (CBND), cannabielsoin (CBE), cannabielsoic acid A (CBEA-A), Cannabielsoic acid B (CBEA-B), cannabicyclol (CBL), cannabicycloic acid (CBLA), cannabicyclovarin (CBLV), cannabitriol (
  • the cannabinoid within the conjugate is CBN.
  • the cannabinoid is linked, via a linker, to a phospholipid (PL).
  • a phospholipid it is to be understood to encompass any member of lipids having a glycerol backbone (glycerophospholipids, GPLs), a sphingosine-backbone (SPLs) or an alkylphospholipid backbone (Alkyl-GPLs) each having at least one fatty acid linked with an ether bond at the sn-1 of the glycerol backbone.
  • GPLs glycerophospholipids
  • SPLs sphingosine-backbone
  • Alkyl-GPLs alkylphospholipid backbone
  • linked to the backbone there is a phosphate carrying a polar headgroup.
  • the phospholipid can be represented by the general formula (II): wherein
  • FA represents a glycerol backbone or a sphinogosine backbone carrying one or two acyl, alkyl or alkenyl chains, which may be the same or different;
  • X represents an oxygen or a hydrophilic head group to which said cleavable linker is bound (not illustrated in formula II).
  • the phospholipid is a glycerophospholipid, namely, FA comprises a glycerol backbone or a sphingosine.
  • FA is a glycerol backbone.
  • X is oxygen to which the cleavable linker is bound.
  • X is the phospholipid polar headgroup to which the cleavable linker is bound.
  • At least one, preferably two of the hydroxyl groups of the glycerol backbone is substituted by, respectively, one or two of an acyl, alkyl or alkenyl chains and the third hydroxyl group of the glycerol backbone is substituted by a phosphate group carrying a polar headgroup.
  • the acyl, alkyl or alkenyl chains are typically between about 6 and about 24 carbon atoms in length, at times, between about 8 and about 24 carbon atoms in length; or at times between about 10 and about 24 carbon atoms in length; or at times, between about 12 and about 24 carbon atoms in length, and have varying degrees of saturation being fully, partially or non-hydrogenated chains.
  • the cannabinoid is linked to the polar headgroup of the phospholipid via a linking portion/segment, referred to herein as the linker portion.
  • the polar headgroup of the phospholipid is one that is capable of, according to some examples of the present disclosure, reacting with maleic anhydride (MA).
  • the reaction between the cannabinoid and the polar headgroup of the PL can be in the presence of a base, including organic base, e.g. pyridine and/or inorganic base, as further described below.
  • a base including organic base, e.g. pyridine and/or inorganic base, as further described below.
  • the polar headgroup is selected from the group consisting of serine (phosphatidylserine, PS), ethanolamine (phosphatidylethanolamine, PE), inositol (phosphatidylinositol, PI), glycerol (phosphatidylglycerol, PG).
  • the phospholipid has a glycerol backbone to which C10-C24 fatty acids (which may be the same or different) are bound to the sn-1 and sn-2 positions.
  • the phospholipid is l,2-Dilauroyl-sn-glycero-3 -phosphorylethanolamine namely, a glycerol backbone comprising a medium chain (12:0) lauric acid at the sn-1 and sn-2 positions, and the phosphorylethanolamine at the sn-3 position.
  • the polar headgroup is ethanolamine, i.e. the phospholipid is PE.
  • the phospholipid moiety comprises PS.
  • the phospholipid moiety comprises PI.
  • the phospholipid moiety comprises PG.
  • the phospholipid is a sphingomyelin.
  • the sphingomyelins consist of a ceramide unit with a phosphorylcholine moiety attached to position 1 and thus in fact is an N-acyl sphingosine.
  • the phosphocholine moiety in sphingomyelin contributes the polar head group of the sphingomyelin.
  • the cannabinoid-lipid conjugate is represented by the general formula (la): wherein the Ri and R2, each represent independently, a saturated or unsaturated acyl, alkyl, alkyl ether or alkenyl chain, or at least one of Ri and R2 is a hydrogen.
  • position 2a marked in formula la is the position that occupies a hydroxyl group when the cannabinoid (in this specific case CBD) is in its free form.
  • cannabinoid-lipid conjugate is represented by the general formula (la), Ri and R2 are identical.
  • Ri and R2 are each an acyl chain.
  • Ri and R2 are each -C(0)-(CH2)IOCH3 chains.
  • the cannabinoid-lipid conjugate (CBD-MA-DLPE) is represented by the general formula (lb): 3-((hydroxy(2- ((E)-4-(((l'R,2 'R)-6-hydroxy-5 '-methyl-4-pentyl-2 '-(prop-l-en-2-yl) l',2', 3',4'- tetrahydro-[ 1, 1 '-biphenyl ]-2-yl)oxy)-4-oxobut-2 enamido)ethoxy)phosphoryl) oxy) propane-1, 2-diyl didodecanoate
  • the conjugate such as that of formula (lb) can be characterized by full NMR analysis and by mass spectroscopy (MS).
  • Mass spectra can be conducted for characterizing the conjugate, using LC-MS, ESI, positive ionization.
  • NMR Nuclear Magnetic Resonance
  • the NMR spectra can be performed for 1 H, 13 C and 15 N, and 31 P, at 278°C, in CDCh containing tetramethylsilane (TMS) as internal reference.
  • TMS tetramethylsilane
  • the conjugate of formula (lb) is characterized by at least the following NMR peaks of Table 2 provided below and constituting and integral part of the presently disclosed subject matter.
  • the presently disclosed subject matter also provides a method for producing the cannabinoid-lipid conjugate disclosed herein.
  • the method disclosed herein comprises:
  • reaction with maleic anhydride can be conducted in the presence of a base.
  • the base can be an organic base and/or an inorganic base.
  • the base is an organic base.
  • the organic base is selected from the group consisting of pyridine, halo-pyridine, imidazole, N- methylimidazole, triethylamine.
  • the organic base is pyridine.
  • the reaction can be carried out in the presence of inorganic bases.
  • the inorganic base is selected from, without being limited thereto, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, etc.
  • the ratio between the PL and the MA in this reaction step is essentially equimolar.
  • an essentially equimolar ratio it is to be understood to be essentially 1 : 1, with some deviations, such as a molar ratio of between about 1 :0.8 and 1 :3, at times, between 1 : 1 and 1 :2, at times, between 1 : 1 and 1 : 1.5.
  • the reaction between the phospholipid and the maleic anhydride provides a PL- MA intermediate.
  • the PL-MA intermediate can be represented by the general formula (III): wherein Ri and R2 have the meaning as defined hereinabove.
  • the PL-MA intermediate is then reacted with the cannabinoid.
  • the PL-MA intermediate prior to reacting with the cannabinoid, can be washed with acid and isolated for further and/or other uses.
  • Non-limiting examples for acids suitable for washing the PL-MA intermediate include inorganic acids, such as HC1 (preferably diluted to about IM) and KHSO4 (also preferably diluted to about IM).
  • the PL-MA intermediate with or without the washing with the acid, is dried prior to the reaction with the cannabinoid.
  • the reaction of the PL-MA intermediate with the cannabinoid is in the presence of a carboxyl activating agent and an esterification agent.
  • carboxyl activating agent is a carbodiimide.
  • the carbodiimide is selected from the group consisting of N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HC1), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC).
  • EDC-HC1 N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • DCC dicyclohexylcarbodiimide
  • DIC diisopropylcarbodiimide
  • the carbodiimide is EDC-HC1.
  • the carboxyl activating agent is a triazole compound.
  • triazoles include hydroxybenzotriazole (HOBt), 1 -hydroxy-7 -azab enzotirazole (HOAt), Cl-HOBt, NO2- HOBt, CFs-HOBt, all commonly used as coupling additives to increase reactivity of leaving groups.
  • the carboxy activating agent is an HOBt-based aminium/phosphonium salt, including, without being limited thereto, benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), O-(lH-6-Chlorobenzotriazole- 1 -yl)- 1 , 1 ,3 ,3 - tetramethyluronium hexafluorophosphate (HA
  • the esterification agent is an organic base.
  • the organic base is selected from the group consisting of 4-Dimethylaminopyridine (DMAP), triethylamine (EtsN), N- Methylmorpholine (NMM), pyridine, N,N-Diisopropylethylamine (DIPEA), imidazole.
  • the esterification agent is DMAP.
  • the reaction between the PL-MA and the cannabinoid is under reflux conditions.
  • the resulting cannabinoid-lipid conjugate can be purified, using any technique known in the art.
  • the resulting conjugate is purified and lyophilized.
  • the herein disclosed method is used for the production of CBD-MA-DLPE conjugate of formula (lb), the method being schematically illustrated in the Scheme (1) below:
  • the cannabinoid-lipid conjugate can be used for the delivery and release of the cannabinoid once within a target body, e.g. within a subject's body or even at a target site.
  • a target body e.g. within a subject's body or even at a target site.
  • PL conjugate is cleavable in the presence of enzymes such as, an esterase.
  • the esterase can be any member of the family of esterase enzyme.
  • the esterase is a carboxylesterase (also known by the term carboxylic-ester hydrolase).
  • the enzyme is any member of the enzymes that fall under the family of carboxylesterase, these include carboxylesterase 1 (CES1), carboxylesterase 2 (CES2), carboxylesterase 3 (CES3), and others.
  • CES1 carboxylesterase 1
  • CES2 carboxylesterase 2
  • CES3 carboxylesterase 3
  • the cannabinoid-lipid conjugate disclosed herein can be integrated into lipid membranes, where the hydrophobic tail(s) of the phospholipid is at least partially embedded (anchored) into the lipid membrane.
  • the cannabinoid-lipid conjugate is anchored onto a lipid-based particle (e.g. nanoparticle), in a non-covalent manner.
  • lipid-based particle when referring to a "lipid-based particle” , it is to be understood to encompass any nano or micron-sized particle having an external lipid membrane.
  • the particle is a nanoparticle.
  • the lipid membrane can be a monolayer, a lipid bilayer, oligolamellar as well as multilamellar type vesicles.
  • the cannabinoid-lipid conjugate either in free form (i.e. unbound to a nanoparticle) or in association with a delivery vehicle, e.g. particle can be formulated with a physiologically acceptable carrier to form an administrable composition.
  • the composition can be, without being limited thereto, a pharmaceutical composition, a cosmetic composition, a nutraceutical composition, a diagnostic composition etc.
  • a method for delivering cannabinoid to a target site comprises administering to a target body including said target site an amount of the presently disclosed cannabinoid-phospholipid conjugate.
  • the target body can include any media in which the release of a free cannabinoid is desired.
  • the media can be an in vitro media, e.g. in diagnostic methods, or a living body, e.g. animal body, where the release and delivery of the free cannabinoid at a target organ, tissue or cell is desired.
  • the target body is a mammal body. In some examples, the target body is the human body. In some examples, the presently disclosed subject matter provides a method of treatment, that involves administering to a subject (e.g. mammalian) in need of treatment and amount of the presently disclosed cannabinoid-phospholipid conjugate.
  • a subject e.g. mammalian
  • the conjugate either in free form or in association with a delivery vehicle, can be administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual in need thereof, the site and method of administration, scheduling of administration, patient age, sex, body weight and other factors known to medical practitioners.
  • the amount of the conjugate will be an effective amount.
  • the term "effective amount” for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve the desired effect from the cannabinoid.
  • the conjugate can be combined with pharmaceutically acceptable carriers, diluents, excipients, additives and adjuvants, as known in the art.
  • the conjugate can be administered by any means known in the art, including, without being limited thereto, intra-abdominal, intra-amnionic, intra-arterial, intraarticular, intra-biliary, intra-cardiac, intra-cartilaginous, intra-caudal, intra-cavernous, intra-cerebral, intra-cistemal, intra-comeal, intra-coronal, intra-coronary, intra-corporus cavernosum, intra-dermal, intradiscal, intra-ductal, intra-duodenal, intra-dural, intraepidermal, intra-esophageal, intra-gastric, intra-gingival, intra-ileal, intra-lesional, intralymphatic, intra-medullary, intra-meningeal, intra-muscular, intra-ocular, intra-ovarian, intra-pericaridal, intra-peritoneal, intra-pleural, intra-prostatic, intra-pulmonary, intra- sinal, intra-spinal,
  • cannabinoid includes one or more cannabinoids.
  • the term “comprising” is intended to mean that the recited elements but not excluding other elements.
  • the term “consisting essentially of' is used to define the recited elements but exclude other elements that may have an essential significance on essence of the disclosed subject matter. "Consisting of' shall thus mean excluding more than trace elements of such other elements. Embodiments defined by each of these transition terms are within the scope of this invention.
  • the procedure for synthesizing the cannabinoid-PL conjugate follows the Scheme provided above and involved connecting the DLPE to maleic anhydride to form DLPE-MA and then the coupling of the DLPE-MA to the CBD to form the conjugate.
  • the PL connection to maleic anhydride was in an organic solvent with addition of an organic base.
  • the second coupling of PL-MA approach is performed with any cannabinoid such as CBD, CBG, CBN, CBDV, CBD A, THC and any functional analogues thereof.
  • the PL-MA was conjugated to CBD can be used on any other cannabinoid (CBD, CBG, CBN, CBDV, THC etc. and any functional analogues thereof)
  • Table 1 provides the materials used in the non-limiting example: Table 1: list of materials
  • the resulting DLPE-MA was analyzed by LC-MS, as shown in Figure 1. Specifically, under the conditions employed, there was obtained a clear peak. According to LC-MS, there was a fit mass 678 [M+H] + .
  • the product was analyzed by LC-MS and NMR.
  • the mass identification was obtained on a negative mode and was shown to be m/z: 972.5 [M-H]-.
  • the NMR data is provided in Table 2.
  • reaction mixture was then quenched and extracted with IM HC1, and then the organic phase was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated.
  • the crude CBD-MA-DLPE was purified on silica gel column chromatography using DCM and MeOH as the eluent (Gradient from 0% MeOH up to 20% MeOH in DCM).
  • the desired CBD-MA-DLPE product was obtained as solid powder after evaporation and analyzed.
  • the CBD-MA-DLPE product was then analyzed by HPLC, under the following conditions
  • HPLC column Luna Omega 3 pm polar C18 100 °A, 150 X 4.6 mm
  • the mobile phase gradient program was as follows: The HPLC results are provided in Figure 3A.
  • Figure 3B provides the UV absorbance of the resulting CBD-MA- DLPE product and Figure 3C provides the H-NMR (400MHz) spectrum.
  • FIG. 3A-3B A computational presentation of the resulting DLPE-MA-CBD conjugate in accordance with Examples 1A-1B is provided in Figures 3A-3B provide. These presentations illustrate the phosphorous group to which the two fatty acid chains are linked, the cleavable linker and the CBD group (Fig. 3 A) and the spatial configuration of the conjugate, similarly pointing at the phosphorous group to which the two fatty acid chains are linked, the cleavable linker and the CBD group (Fig. 3B).

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Abstract

La présente divulgation concerne un conjugué cannabinoïde-phospholipide, le cannabinoïde étant lié de manière covalente, par l'intermédiaire d'un lieur clivable, à un groupe de tête polaire du phospholipide. La divulgation concerne également un procédé permettant d'obtenir le conjugué, le procédé comprenant (a) la réaction du phospholipide (PL) dissous dans un solvant organique avec de l'anhydride maléique (MA) pour obtenir un intermédiaire PL-MA; et (b) la réaction dudit intermédiaire PL-MA avec le cannabinoïde en présence d'un agent d'activation carboxyle et d'un agent d'estérification pour obtenir un mélange réactionnel comprenant ledit conjugué. La divulgation concerne en outre des utilisations du conjugué.
PCT/IL2022/051012 2021-09-22 2022-09-22 Conjugués cannabinoïdes-lipides, leurs procédés de production et leurs utilisations WO2023047399A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023009817A3 (fr) * 2021-07-29 2023-06-29 Emory University Promédicaments cannabinoïdes à base de phosphate

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020177609A1 (en) * 2001-03-23 2002-11-28 Swindell Charles S. Fatty alcohol drug conjugates
WO2020191477A1 (fr) * 2019-03-22 2020-10-01 Integrated Nanotherapeutics Inc. Conjugué lipidique préparé à partir d'un fragment squelette

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020177609A1 (en) * 2001-03-23 2002-11-28 Swindell Charles S. Fatty alcohol drug conjugates
WO2020191477A1 (fr) * 2019-03-22 2020-10-01 Integrated Nanotherapeutics Inc. Conjugué lipidique préparé à partir d'un fragment squelette

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023009817A3 (fr) * 2021-07-29 2023-06-29 Emory University Promédicaments cannabinoïdes à base de phosphate

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